This invention relates to heterocyclic pharmaceuticals, and more particularly, to 2-arylimino heterocycles, pharmaceutical compositions containing them, and their use in modulating progesterone receptor mediated processes.
An agent which binds to the progesterone receptor may be employed for a wide variety of indications, including those shown in the lettered paragraphs below:
A1) to enhance bone formation in bone weakening diseases, for the prevention of and/or treatment of osteopenia or osteoporosis (Manzi, et al., J. Soc. Gynecol. Invest., 1, 302 (1994); Scheven, et al., Biochem. Biophys. Res. Commun., 186, 54 (1992); Verhaar, et al., Bone, 15, 307 (1904); Ontjes, In xe2x80x9cCalcium and Phosphorus in Health Diseasesxe2x80x9d, Anderson and Garner (Eds.), CRC Press, 207 (1996); Scheven et al., Biochem. Biophys. Res. Commun., 186, 54 (1992)) including corticosteroid-induced osteoporosis (Picardo, et al., Drug Safety 15, 347 (1996)), postmenopausal osteoporosis, or Paget""s disease;
A2) as an agent to enhance fracture healing;
B1) as a female contragestive agent, (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Heikinheimo Clin. Pharmacokinet., 33, 7 (1997); Li et al., Adv. Contracept., 11, 285 (1995); Spitz et al., Adv. Contracept. 8, 1 (1992); Spitz et al., Annu. Rev. Pharmacol. Toxicol., 36, 47 (1996));
B2) for prevention of endometrial implantation (Cadepond et al., Annu. Rev. Med., 48, 129 (1997));
B3) for the induction of labor (Heikinheimo Clin. Pharmacokinet., 33, 7 (1997); Karalis et al., Ann. N. Y. Acad. Sci., 771, 551 (1995)), including the case of foetus mortus (Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Cadepond et al., Annu. Rev. Med., 48, 129 (1997));
B4) for treatment of luteal deficiency (Pretzsh et al., Zentralbl. Gynaekol., 119 (Suppl. 2), 25 (1997); Bezer et al., In xe2x80x9cMolecular and Cellular Aspects of Periimplantation Processesxe2x80x9d, Dey (Ed.), Springer-Verlag, p. 27 (1995));
B5) to enhance recognition and maintanence of pregnancy (Bezer et al., In xe2x80x9cMolecular and Cellular Aspects of Periimplantation Processesxe2x80x9d, Dey (Ed.), Springer-Verlag, p. 27 (1995));
B6) for counteracting preeclampsia, eclampsia of pregnancy and preterm labor (Yallampalli et al., WO 97/34,922);
B7) for the treatment of infertility, including promotion of spermatogenesis, the induction of the acrosome reaction, oocyte maturation, and in vitro fertilization of oocytes (Baldi et al., J. Steroid Biochem. Mol. Biol., a53, 199 (1995); Baldi et al., Trends Endocrinol. Metab., 6, 198 (1995); Blackwell et al., Colloq. INSERM, 236, 165 (1995); Blackmore et al., Cell. Signalling, 5, 531 (1993); Cork et al., Zygote, 2, 289 (1994); Meizel, Biol. Reprod., X, 56, 569 (1997));
C1) for treatment of dysmenorrhea (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995));
C2) for treatment of dysfunctional uterine bleeding (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995));
C3) for treatment of ovarian hyperandrogynism (Schaison et al., Androg. Excess Disord. Women, 715 (1997));
C4) for treatment of ovarian hyperaldosteronism (Adashi et al., Keio J. Med., 44, 124 (1995));
C5) for treatment of premenstral syndrome and/or premenstral tension (Mortola, Curr. Opin. Endocrinol. Diabetes, 2, 483 (1995)); Adashi et al., Keio J. Med., 44, 124 (1995));
C6) for treatment of perimenstrual behavior disorders (Constant et al., Hormone Res., 40, 141 (1993));
C7) for treatment of climeracteric disturbance, i.e. menopause transition (Adashi et al., Keio J. Med., 44, 124 (1995)) including hot flushes (Sarrel, Int. J. Fertil. Women""s Med., 42, 78 (1997); Bxc3xa4strxc3x6m et al., Ciba Found. Symp., 121, 171 (1995)), mood changes (Bxc3xa4strxc3x6m et al., Ciba Found. Symp., 121, 171 (1995)), sleep disturbance (Sarrel, Int. J. Fertil. Women""s Med., 42, 78 (1997)) and vaginal dryness (Sarrel, Int. J. Fertil. Women""s Med., 42, 78 (1997));
C8) for enhancement of female sexual receptivity (Dei et al., Eur. J. Contracept. Reprod. Health Care, 2(4), 253 (1997); McCarthy et al., Trends Endocrinol. Metab., 7, 327-333 (1996); Mani et al., Horm. Behav., 31, 244 (1997)) and male sexual receptivity (Johnson et al., In xe2x80x9cEssential Reproduction, 2nd ed., Blackwell Scientific Pub., London p177 (1984));
C9) for treatment of post menopausal urinary incontinence (Mxc3xa4kinen et al., Maturitas, 22, 233 (1995); Batra et al., J. Urology, 138, 1301 (1987));
C10) to improve sensory and motor functions (Bxc3xa4strxc3x6m et al., Ciba Found. Symp., 121, 171 (1995));
C11) to improve short term memory (Bxc3xa4strxc3x6m et al., Ciba Found. Symp., 121, 171 (1995));
C12) for treatment of postpartum depression (Dalton, Practitioner, 229, 507 (1985));
C13) for treatment of genital atrophy (Sarrel, Int. J. Fertil. Women""s Med., 42, 78 (1997));
C14) for prevention of postsurgical adhesion formation (Ustun, Gynecol. Obstet. Invest., 46, 202 (1998));
C15) for regulation of uterine immune function (Hansen et al., J. Reprod. Fertil., 49(Suppl.), 69 (1995));
C16) for prevention of myocardial infarction (Sarrel, Int. J. Fertil. Women""s Med., 42, 78 (1997));
D1) for hormone replacement therapy (Casper et al., J. Soc. Gynecol. Invest., 3, 225 (1996));
E1) for treatment of cancers, including breast cancer (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997)), uterine cancer (Heikinheimo Clin. Pharmacokinet., 33, 7 (1997)), ovarian cancer (Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997); Hughes, WO 98/10,771), and endometrial cancer (Satyaswaroop, Contrib. Oncol., 50, 258 (1995); Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997));
E2) for treatment of endometriosis (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Edmonds, Br, J. Obstet. Gynaecol., 103 (Suppl. 14), 10 (1996); Adashi et al., Keio J. Med., 44, 124 (1995));
E3) for treatment of uterine fibroids (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Adashi et al., Keio J. Med., 44, 124 (1995));
F1) for treatment of hirsutism (Orentreich et al., U.S. Pat. No. 4,684,635; Azziz et al., J. Clin. Endocrinol. Metab., 80, 3406 (1995));
F2) for inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11 (1978));
G1) as a male contraceptive (Hargreave et al., Int. Congr., Symp. Semin. Ser., 12, 99 (1997); Meriggiola et al., J. Androl., 18, 240 (1997));
G2) as an abortifacient (Michna et al., Pharm. Ztg., 141, 11 (1996)); and
H1) for the promotion of mylin repair (Baulieu et al., Cell. Mol. Neurobiol., 16, 143 (1996); Baulieu et al., Mult. Scler., 3, 105 (1997); Schumaker et al., Dev. Neurosci., 18, 6 (1996); Koenig et al., Science, 268, 1500 (1995)).
Currently, progesterone or progestins alone or in combination with estrogens are clinically indicated: for contraception (Merck Manual; Merck and Co. (1992)); for treatment of gastrointestional bleeding due to arteriovenous malformations (Merck Manual; Merck and Co. (1992)); for treatment of recurrent metatarsal stress fractures complicated by oligiomenorrhea or amenorrhea (Merck Manual; Merck and Co. (1992)); for treatment of premenstral syndrome (PMS, premenstral tension; Merck Manual; Merck and Co. (1992)); for postmenopausal hormone replacement therapy (Merck Manual; Merck and Co. (1992)); for treatment of hot flashes and subsequent insomnia and fatigue during menopause (Merck Manual; Merck and Co. (1992)); for treatment of dysfunctional uterine bleeding when pregnancy is not desired (Merck Manual; Merck and Co. (1992)); and for suppression of endometriosis (Merck Manual; Merck and Co. (1992)), breast cancer (Merck Manual; Merck and Co. (1992)), endometrial cancer (Merck Manual; Merck and Co. (1992)), or luteal insufficiency (Merck Manual; Merck and Co. (1992)). For example, medroxyprogesterone, a progestin, alone or in combination with estrogens is indicated for prevention of osteoporosis, treatment of vulvar and/or vaginal atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrehea, treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, prevention of pregnancy, or as adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma (Merck Manual; Merck and Co. (1998)).
This invention provides nonsteroidal 2-arylimino- and 2-heteroarylimino-heterocyclic compounds which have affinity for the progesterone receptor, and therefore can act as progestins and/or antiprogestins thus modulating progesterone receptor mediated processes.
This invention relates to compounds having the formula (I) 
wherein
R is
aryl of 6-14 carbons; or
heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene;
R1 is
alkyl of 1-10 carbons;
cycloalkyl of 3-12 carbons and containing 1-3 rings;
heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S;
alkenyl of 2-10 carbons;
cycloalkenyl of 5-12 carbons and containing 1-3 rings; or
alkynyl of 3-10 carbons;
R2, R3, and R4 are independently selected from the group consisting of
H;
alkyl of 1-10 carbons;
cycloalkyl of 3-12 carbons;
alkenyl of 2-10 carbons;
cycloalkenyl of 5-12 carbons;
aryl of 6-13 carbons;
heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5; wherein
R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;
halogen; and
xe2x95x90O, representing two of the groups R2, R3, and R4;
X is O or S(O)y; wherein
y is 0, 1,or 2;
n is 2, 3, 4, or 5;
p is the sum of non-H substituents R2, R3, and R4;
T is a substituent selected from the group consisting of
alkyl of 1-4 carbons;
alkoxy of 1-4 carbons;
aryl of 6-10 carbons;
CO2H;
CO2R5;
alkenyl of 2-4 carbons;
alkynyl of 2-4 carbons;
C(O)C6H5;
C(O)N(R6)(R7); wherein
R6 is H or alkyl of 1-5 carbons; and
R7 is H or alkyl of 1-5 carbons;
S(O)yxe2x80x2R8; wherein
yxe2x80x2 is 1 or 2; and
R8 is alkyl of 1-5 carbons;
O2F;
CHO;
OH;
NO2;
CN;
halogen;
OCF3;
N-oxide;
Oxe2x80x94C(R)2xe2x80x94O, the oxygens being connected to adjacent positions on R; and wherein
R9 is H, halogen, or alkyl of 1-4 carbons;
C(O)NHC(O), the carbons being connected to adjacent positions on R; and
C(O)C6H4, the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R;
t is 1-5;
provided that when substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, aryl of 6-10 carbons, CO2R5, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C(O)C6H5, C(O)N(R6)(R7), S(O)yxe2x80x2R8, Oxe2x80x94C(R9)2xe2x80x94O, or C(O)C6H4, then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; CO2R5; CO2H; C(O)N(R6)(R7); CHO; OH; NO2; CN; halogen; S(O)yR8; or xe2x95x90O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;
G is a substituent selected from the group consisting of halogen;
OH;
OR5;
xe2x95x90O, representing two substituents G;
alkyl of 1-4 carbons;
alkenyl of 1-4 carbons;
cycloalkyl of 3-7 carbons;
heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
cycloalkenyl of 5-7 carbons,
heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5;
C(O)N(R6)(R7);
aryl of 6-10 carbons;
heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
NO2;
CN;
S(O)yR8;
SO3R8; and
SO2N(R6)(R7);
g is 0-4, with the exception of halogen, which may be employed up to the perhalo level;
provided that when substituent 0 is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;
Q is a substituent selected from the group consisting of
alkyl of 1-4 carbons;
haloalkyl of 1-4 carbons;
cycloalkyl of 3-8 carbons;
alkoxy of 1-8 carbons;
alkenyl of 2-5 carbons;
cycloalkenyl of 5-8 carbons;
aryl of 6-10 carbons;
heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5;
xe2x95x90O, representing two substituents Q;
OH;
halogen;
N(R6)(R7);
S(O)yR8;
SO3R8; and
SO2N(R6)(R7);
q is 0-4
provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and
with the further provisos that:
a) two of (Q)qR1, (Q)qR2, (Q)qR3, and (Q)qR4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S;
b) when n=2 or 3, at least one of R2, R3, and R4 is other than H;
c) when n=2, and X=O, if t=1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3-oxazolidine ring must bear a substituent;
d) when n=3 and X=O, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy;
e) when n=2 or 3 and X=O or S, then the sum of non-hydrogen atoms in R1, R2, R3, and R4 is at least 5;
f) when n=2, X=O, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2- and 4-positions, then the 5-position of R bears H;
g) when n=2 and X=O, the 4-position of the 1,3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent;
h) when n=2, X=S(O)y, the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R1 is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent;
i) when n=4, X=S, and G is CO2R5, then R5 contains at least two carbons;
and pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions which include a compound of formula (I) as disclosed above, plus a pharmaceutically acceptable carrier.
As a result of their affinity for the progesterone receptor and their resultant ability to act as progestins and/or antiprogestins, and thus modulate progesterone receptor mediated processes, the compounds of this invention, as well as certain related compounds of the prior art, are believed to be useful for the purposes listed in the background section. It is to be noted that the definition of the set of compounds for use in the claimed method of treatment (formula II) is broader than the set of compounds defined by formula I, because the treatment method may employ certain compounds of the prior art which have not been recognized previously as being useful for this purpose. Accordingly, the invention relates further to a method of treating a mammal to achieve an effect, wherein the effect is:
A1) enhancement of bone formation in bone weakening diseases for the treatment or prevention of osteopenia or osteoporosis;
A2) enhancement of fracture healing;
B1) activity as a female contragestive agent;
B2) prevention of endometrial implantation;
B3) induction of labor;
B4) treatment of luteal deficiency;
B5) enhanced recognition and maintanence of pregnancy;
B6) counteracting of preeclampsia, eclampsia of pregnancy, and preterm labor;
B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes;
C1) treatment of dysmenorrhea;
C2) treatment of dysfunctional uterine bleeding;
C3) treatment of ovarian hyperandrogynism;
C4) treatment of ovarian hyperaldosteronism;
C5) alleviation of premenstral syndrome and of premenstral tension;
C6) alleviation of perimenstrual behavior disorders;
C7) treatment of climeracteric disturbance, including, menopause transition, mood changes, sleep disturbance, and vaginal dryness;
C8) enhancement of female sexual receptivity and male sexual receptivity;
C9) treatment of post menopausal urinary incontinence;
C10) improvement of sensory and motor functions;
C11) improvement of short term memory;
C12) alleviation of postpartum depression;
C13) treatment of genital atrophy;
C14) prevention of postsurgical adhesion formation;
C15) regulation of uterine immune function;
C16) prevention of myocardial infarction;
D1) therapy for hormone replacement;
E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer;
E2) treatment of endometriosis;
E3) treatment of uterine fibroids;
F1) treatment of hirsutism;
F2) inhibition of hair growth;
G1) activity as a male contraceptive;
G2) activity as an abortifacient; and
H1) promotion of mylin repair;
which comprises administering to said mammal an effective amount of a compound of the formula (II) 
wherein
R is
aryl of 6-14 carbons; or
heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene;
R1 is
alkyl of 1-10 carbons;
cycloalkyl of 3-12 carbons and containing 1-3 rings;
heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S;
aryl of 6-10 carbons;
heteroaryl of 3-9 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S;
alkenyl of 2-10 carbons;
cycloalkenyl of 5-12 carbons and containing 1-3 rings; or
alkynyl of 3-10 carbons;
R2, R3, and R4 are independently selected from the group consisting of
H;
alkyl of 1-10 carbons;
cycloalkyl of 3-12 carbons;
alkenyl of 2-10 carbons;
cycloalkenyl of 5-12 carbons;
aryl of 6-13 carbons;
heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5; wherein
R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;
halogen; and
xe2x95x90O, representing two of the groups R2, R3, and R4;
X is O or S(O)y; wherein
y is 0, 1, or 2;
n is 2, 3, 4, or 5;
p is the sum of non-H substituents R2, R3, and R4;
s represents the number of double bonds in the ring, and is 0, 1, or 2;
T is a substituent selected from the group consisting of
alkyl of 1-4 carbons;
alkoxy of 1-4 carbons;
aryl of 6-10 carbons;
CO2H;
CO2R5;
alkenyl of 2-4 carbons;
alkynyl of 2-4 carbons;
C(O)C6H5;
C(O)N(R6)(R7); wherein
R6 is H or alkyl of 1-5 carbons; and
R7 is H or alkyl of 1-5 carbons;
S(O)yxe2x80x2R8; wherein
yxe2x80x2 is 1 or 2; and
R8 is alkyl of 1-5 carbons;
SO2F;
CHO;
OH;
NO2;
CN;
halogen;
OCF3;
N-oxide;
Oxe2x80x94C(R9)2xe2x80x94O, the oxygens being connected to adjacent positions on R; and wherein
R9 is H, halogen, or alkyl of 1-4 carbons;
C(O)NHC(O), the carbons being connected to adjacent positions on R; and
C(O)C6H4, the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R;
t is 1-5;
provided that when substituent moiety T is alkyl of 1-4 carbons; alkoxy of 1-4 carbons; aryl of 6-10 carbons; CO2R5; alkenyl of 2-4 carbons; alkynyl of 2-4 carbons; C(O)C6H5; C(O)N(R6)(R7); S(O)yxe2x80x2R8; Oxe2x80x94C(R9)2xe2x80x94O, or C(O)C6H4, then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; CO2R5; CO2H; C(O)N(R6)(R7); CHO; OH; NO2; CN; halogen; S(O)yR8; or xe2x95x90O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;
G is a substituent selected from the group consisting of
halogen;
OH;
OR5;
xe2x95x90O, representing two substituents G;
alkyl of 1-4 carbons;
alkenyl of 1-4 carbons:
cycloalkyl of 3-7 carbons;
heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
cycloalkenyl of 5-7 carbons;
heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5;
C(O)N(R6)(R7);
aryl of 6-10 carbons;
heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S;
NO2;
CN:
S(O)yR8;
SO3R8; and
SO2N(R6)(R7);
g is 0-4, with the exception of halogen, which may be employed up to the perhalo level;
provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;
Q is a substituent selected from the group consisting of
alkyl of 1-4 carbons;
haloalkyl of 1-4 carbons;
cycloalkyl of 3-8 carbons;
alkoxy of 1-8 carbons;
alkenyl of 2-5 carbons;
cycloalkenyl of 5-8 carbons;
aryl of 6-10 carbons;
heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S;
xe2x95x90O, representing two substituents Q;
OH;
halogen;
N(R6)(R7);
S(O)yR8;
SO3R8; and
SO2N(R6)(R7);
q is 0-4
provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and
with the further proviso that two of (Q)qR1, (Q)qR2, (Q)qR3, and (Q)qR4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S;
and pharmaceutically acceptable salts thereof.
The compounds of formula (I) have been defined broadly in the summary above. In the compounds of formula (I), the following group preferences apply:
R is preferably phenyl or pyridyl.
R1 is preferably alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons and containing 1-3 rings, or alkynyl of 3-10 carbons. R1 is more preferably alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons, or cycloalkenyl of 5-12 carbons and containing 1-3 rings.
R2, R3, and R4 are preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons, or xe2x95x90O, in which the carbonyl represents two of the groups R2, R3, and R4. R2, R3, and R4 are more preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons, or cycloalkenyl of 5-12 carbons.
X is preferably 0 or S(O)y, wherein y is 0, 1, or 2.
The subscript n, representing the number of carbons in the ring, is preferably 2 or 3.
The subscript p, representing the sum of non-H substituents R2, R3, and R4, is preferably 1 or 2.
T is a substituent preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, NO2, CN, and halogen. T is more preferably alkyl of 1-4 carbons, alkenyl of 2-4 carbons, NO2, CN, or halogen.
The subscript t, representing the number of substituents T, is 1-5, more preferably 1-3.
When substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, or alkynyl of 2-4 carbons, then T optionally may bear secondary substituents preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, CO2R5, CO2H, C(O)N(R6)(R7), CHO, OH, NO2, CN, halogen, (O)yR8, and xe2x95x90O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level.
As employed in this application, the term xe2x80x9csecondary substituentxe2x80x9d means a substituent on a substituent, not xe2x80x9csecondaryxe2x80x9d as used in defining the degree of substitution at a carbon.
As employed in this application, the terms xe2x80x9chaloalkylxe2x80x9d and xe2x80x9chalocycloalkylxe2x80x9d are employed to refer to groups which may contain halogen atoms in any number up to the per-halo level.
G is preferably selected from the group consisting of halogen, ORE, alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, aryl of 6-10 carbons, and CN. G is more preferably halogen, alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, or aryl of 6-10 carbons.
The subscript g, representing the number of substituents G, is 0-4, more preferably 0-2, with the exception of halogen, which may be employed up to the perhalo level.
Q is preferably selected from the group consisting of alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbons, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons, CO2R5, xe2x95x90O, 1OH, halogen, N(R6)(R7), and S(O)y8. Q is more preferably alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbons, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons, or halogen.
The present invention also includes pharmaceutically acceptable salts of the compounds of Formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+ Na+ or K+), alkaline earth cations (e.g., Mg+2, Ca+2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to the skilled in the art. The present invention encompasses any racemic or optically active forms of compounds described in Formula I which possess progesterone receptor binding activity.
The most preferred 2-imino-1,3-thiazolidines and ring expanded homologues of 2-imino-1,3-thiazolidines of the invention are the following:
(4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-1,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl-1,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isopropyl-1,3-thiazolidine;
(4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H-1,3-thiazine;
(4S)-2-(4-nitro-1-naphthylimino)-3-cyclopentyl-4-((1R)-1-hydroxyethyl)-1,3-thiazolidine;
2-(4-cyano-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4]nonane;
2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;
2-(4-cyanophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;
2-(4-cyano-2-methylphenylimino)-1-isobutyl-3thia-1-azaspiro[4.4]nonane;
2-(4-cyano-2,3-dimethylphenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;
2-(4-cyano-2-methylphenylimino)-1-(1-ethyl-1-propyl)-3-thia-1-azaspiro[4.4]nonane;
2-(4-cyano-1-naphthylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-1-(propenyl)-3-thia-1-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-1-isopropyl-3-thia-1-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;
2-(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro[4.4]nonane;
2-(2,3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane; and
2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
The most preferred thiazolidin-4-ones of the invention are the following:
2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one;
2-(3-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one;
2-(3-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one;
2-(3-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-ethyl)-1,3-thiazolidin-4-one,;
2-(3-methyl-4-nitrophenylimino)-3-(2-cyclohexyl-1-ethyl)-1,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-1,3-thiazolidin-4-one; and
1-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin-4-one.
The most preferred oxazolidines of the invention are the following:
2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-oxazolidine;
1-cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa-1azaspiro[4.4]nonane;
1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane; and
1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
The therapeutic agents of the invention may be employed alone or concurrently with other therapies. For example, when employed as in A1 or A2, the agent may be used in combination with a calcium source, vitamin D or analogues of vitamin D, and/or antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, treatment with calcitonin or a calcitonin analogue, or treatment with a bisphosphonate such as alendronate. When employed as in B1 through B7, the agent may be used with therapies such as estrogen replacement therapy. When employed as in C1 through C16, E1 through E3, or F1 or F2, the agent may be used concurrently with therapies such as estrogen replacement therapy and/or a gonadotropin-releasing hormone agonist. When employed as in G1 or G2, the agent may be used concurrently with therapies such as an androgen.
The method of the invention is intended to be employed for treatment of progesterone receptor mediated conditions in both humans and other mammals.
The compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term xe2x80x98administered by injectionxe2x80x99 includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; xe2x80x9cTransdermal Controlled Systemic Medicationsxe2x80x9d; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 Mar. 3, 1994). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weigh t of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
The entire disclosures of all applications, patents and publications cited above and below are hereby incorporated by reference.
The compounds of Formula I may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods shown below as well as by other reactions and procedures known to the skilled in the art. Nevertheless, the following general preparative methods are presented to aid practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way.
As employed herein, the following terms have the indicated meanings.
Aryl amines, aryl isocyanates, aryl isothiocyanates, unsymmetrical aryl thiourea, aryl isocyanate dichlorides and 2-arylimino-1,3-heterocycles may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985)). For example, aryl isocyanates (2) are available from the reaction of phosgene, or a phosgene equivalent, such as carbonyl diimidazole, diphosgene or triphosgene, and aryl isothiocyanates (3) are available from reaction of an aryl amine with thiophosgene or a thiophosgene equivalent, such as thiocarbonyl diimidazole (Scheme I). Also, many aryl isocyanates and aryl isothiocyanates are commercially available. Reaction of an aryl isothiocyanate with a primary amine then affords thiourea 4 (Hahn et al. Han""guk Nonghwa Hakhoechi 1997,40, 139; Dxc3xcrr U.S. Pat. No. 4,079,144; Enders U.S. Pat. No. 4,148,799). 
As shown in Scheme II, thioureas react with xcex1-haloketones, e.g. xcex1-bromoketone 5, to afford, after dehydration, the thiazoline (6) (Hahn et al. Han""guk Nonghwa Hakhoechi 1997,40, 139; Dxc3xcrr U.S. Pat. No. 4,079,144; Enders U.S. Pat. No. 4,148,799). 
Similarly, thioureas react with xcex1-haloacid halides (Giri et al. Asian J. Chem. 1992, 4, 785; Lakhan et al. Agric. Biol. Chem. 1982,46, 557), xcex1-haloacids (Dogan et al. Spectrosc. Lett. 1983, 16, 499; Seada et al. Indian J. Heterocycl. Chem. 1993, 3, 81), and xcex1-haloesters (Seada et al. Indian J. Heterocycl. Chem. 1993, 3, 81) to afford 4-thiazolidinones (10). 
Aryl isothiocyanates (3) also react with allylamines (Tsoi et al. Zh. Org Khim. 1983, 19, 2605) and propargylamines (Azerbaev et al. Khim. Geterotsikl. Soedin. 1972, 471) to form the corresponding thioureas, which on acid treatment afford the 5-substituted thiazolidines (Scheme IV). 
Aryl isothiocyanates may also be reacted with hydroxylamines (17) to form N-hydroxyalkylthiourea 18 (Scheme V). Treatment of the thiourea with acid then leads to 2-imino-1,3-heterocycle 19 (Jen et al. J.Med Chem. 1975, 18, 90; Tyukhteneva et al. Khim. Geterotsikl. Soedin. 1985, 12, 1629; Olszenko-Piontkowa et al. Org. Prep. Proced Int. 11971, 3, 27). Reaction of hydroxyalkylthiourea 18 with SOCl2 affords cloroalkyl analogue 20, which on treatment with base will cyclize to afford heterocycle 19 (Cherbuliez et al. Helv. Chim. Acta 1967, 50, 331; Felix et al. U.S. Pat. No. 4,806,053). 
Alternatively, as shown in Scheme VI, treatment of N-hydroxyalkylthiourea 18 with either HgO or an alkylating agent, such as methyl iodide followed by base affords the corresponding oxygen-containing heterocycle (Jen et al. J.Med. Chem. 1975, 18, 90; Ignatova et al. Khim. Geterotsikl. Soedin. 1974, 354). 
Chloroalkyl isothiocyanates have been reported to react with arylamines to afford the corresponding sulfur 2-phenylimino-1,3-heterocycle (Sagner et al. U.S. Pat. No. 3,651,053; Ibid U.S. Pat. No. 3,737,536). 
Aryl amines react with a formylating source, such as formic acetic anhydride, to form formanilide 25, which may then be oxidatively converted to the aryl isocyanide dichloride (Ferchland et al. DE 3,134,134; for a review, see: Kuehle et al. Angew. Chem. 1967, 79, 663). Aryl isocyanide dichlorides (26) react with hydroxylamines (27) to give oxygen-containing 2-phenylimino-1,3-heterocycle 30 (Wollweber U.S. Pat. No. 3,787,575; Ibid U.S. Pat. No. 3,686,199) and with hydroxylamide 28 to give thiazolidinone 31. In addition, aryl isoyanide dichlorides have been shown to react with aminomercaptans (29) to give the sulfur-containing 2-phenylimino-1,3-heterocycle 32 (Thibault French Patent 1,510,015). 
Treatment of hydroxylamines with CS2 in the presence of base will generate the 1,3-thiaza-2-thione (Scheme IX). It has been reported that thione 34 reacts with SOCl2 to give hydroscopically labile imidate 35, which on treatment with an aryl amine affords the sulfur-containing 2-imino-1,3-heterocycle (Hanefeld et al. Arch. Pharm. 1985, 318, 60; Ibid 1988, 321, 199). 
Both oxygen-containing and sulfur-containing 2-imino-1,3-heterocycles may be further elaborated. Thus, for example, as shown in Scheme X, treatment of N3-unsubstituted 2-phenylimino-1,3-heterocycles with electrophiles, typically in the precense of base, affords the N3-substituted product (Ambartsumova et al. Chem. Heterocycl. Compd. 1997, 33, 475; Mizrakh et a. Khim. Geterotsikl. Soedin. 1990, 563; Olszenko-Piontkowa et al. Org. Prep. Proced. Int. 11971, 3, 27). 
In addition, as shown in Scheme XI, sulfur-containing 2-imino-1,3-heterocycles may be oxidized to the sulfoxide or sulfone (Chizhevskayaet al. Khim. Geterotsikl. Soedin. 1971, 96; Pandey et al. J. Indian Chem. Soc. 1972, 49, 171). 
Detailed examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps.